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Distantly related lipocalins share two conserved clusters of hydrophobic residues: use in homology modeling
Benoit Adam, Benoit Charloteaux, Jerome Beaufays, Luc Vanhamme, Edmond Godfroid, Robert Brasseur, Laurence Lins
BMC Structural Biology , 2008, DOI: 10.1186/1472-6807-8-1
Abstract: The pairwise sequence identity is low among this family, often below 30%, despite a well conserved tertiary structure. Under the 30% identity threshold, alignment methods do not correctly assign and align proteins. The only safe way to assign a sequence to that family is by experimental determination. However, these procedures are long and costly and cannot always be applied. A way to circumvent the experimental approach is sequence and structure analyze. To further help in that task, the residues implicated in the stabilisation of the lipocalin fold were determined. This was done by analyzing the conserved interactions for ten lipocalins having a maximum pairwise identity of 28% and various functions.It was determined that two hydrophobic clusters of residues are conserved by analysing the ten lipocalin structures and sequences. One cluster is internal to the barrel, involving all strands and the 310 helix. The other is external, involving four strands and the helix lying parallel to the barrel surface. These clusters are also present in RaHBP2, a unusual "outlier" lipocalin from tick Rhipicephalus appendiculatus. This information was used to assess assignment of LIR2 a protein from Ixodes ricinus and to build a 3D model that helps to predict function. FTIR data support the lipocalin fold for this protein.By sequence and structural analyzes, two conserved clusters of hydrophobic residues in interactions have been identified in lipocalins. Since the residues implicated are not conserved for function, they should provide the minimal subset necessary to confer the lipocalin fold. This information has been used to assign LIR2 to lipocalins and to investigate its structure/function relationship. This study could be applied to other protein families with low pairwise similarity, such as the structurally related fatty acid binding proteins or avidins.Lipocalins are small secreted proteins (160–200 residues), typically structured in a 8 strands up and down β-barrel. A 310
Ixodes ricinus Tick Lipocalins: Identification, Cloning, Phylogenetic Analysis and Biochemical Characterization
Jér?me Beaufays, Beno?t Adam, Yves Decrem, Pierre-Paul Prév?t, Sébastien Santini, Robert Brasseur, Michel Brossard, Laurence Lins, Luc Vanhamme, Edmond Godfroid
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0003941
Abstract: Background During their blood meal, ticks secrete a wide variety of proteins that interfere with their host's defense mechanisms. Among these proteins, lipocalins play a major role in the modulation of the inflammatory response. Methodology/Principal Findings Screening a cDNA library in association with RT-PCR and RACE methodologies allowed us to identify 14 new lipocalin genes in the salivary glands of the Ixodes ricinus hard tick. A computational in-depth structural analysis confirmed that LIRs belong to the lipocalin family. These proteins were called LIR for “Lipocalin from I. ricinus” and numbered from 1 to 14 (LIR1 to LIR14). According to their percentage identity/similarity, LIR proteins may be assigned to 6 distinct phylogenetic groups. The mature proteins have calculated pM and pI varying from 21.8 kDa to 37.2 kDa and from 4.45 to 9.57 respectively. In a western blot analysis, all recombinant LIRs appeared as a series of thin bands at 50–70 kDa, suggesting extensive glycosylation, which was experimentally confirmed by treatment with N-glycosidase F. In addition, the in vivo expression analysis of LIRs in I. ricinus, examined by RT-PCR, showed homogeneous expression profiles for certain phylogenetic groups and relatively heterogeneous profiles for other groups. Finally, we demonstrated that LIR6 codes for a protein that specifically binds leukotriene B4. Conclusions/Significance This work confirms that, regarding their biochemical properties, expression profile, and sequence signature, lipocalins in Ixodes hard tick genus, and more specifically in the Ixodes ricinus species, are segregated into distinct phylogenetic groups suggesting potential distinct function. This was particularly demonstrated by the ability of LIR6 to scavenge leukotriene B4. The other LIRs did not bind any of the ligands tested, such as 5-hydroxytryptamine, ADP, norepinephrine, platelet activating factor, prostaglandins D2 and E2, and finally leukotrienes B4 and C4.
Exposure of Endothelial Cells to Physiological Levels of Myeloperoxidase-Modified LDL Delays Pericellular Fibrinolysis
Karim Zouaoui Boudjeltia, Jalil Daher, Pierre Van Antwerpen, Nicole Moguilevsky, Paul Delree, Jean Ducobu, Martine Raes, Bassam Badran, Michel Vanhaeverbeek, Dany Brohee, Claude Remacle, Luc Vanhamme
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0038810
Abstract: Background Blood fluidity is maintained by a delicate balance between coagulation and fibrinolysis. The endothelial cell surface is a key player in this equilibrium and cell surface disruptions can upset the balance. We investigated the role of pericellular myeloperoxidase oxidized LDLs (Mox-LDLs) in this balance. Methods and Results We designed a technical device that enabled us to monitor fibrinolysis in real-time at the surface of an endothelial cell line (EA.hy926), and showed that Mox-LDL decreased pericellular fibrinolysis. There were no changes in fibrinolysis when EA.hy926 endothelial cells were exposed to native LDL (24 hours) at doses of 10, 50, 100 and up to 1250 μg/ml. However, treatment of EA.hy926 endothelial cells with 10 and 50 μg/ml of Mox-LDL (physiological serum concentrations) increased the lysis time by 15 and 13%, respectively (p<0.001), although this effect was not present at higher concentrations of 100 μg/ml. This effect was not correlated with any changes in PAI-1 or t-PA or PA Receptor (PAR) expression. No effect was observed at the surface of smooth muscle cells used as controls. Conclusion Our data link the current favorite hypothesis that modified LDL has a causal role in atheroma plaque formation with an old suggestion that fibrin may also play a causal role. Our data help complete the paradigm of atherosclerosis: Modified LDL locally enhances fibrin deposition (present work); fibrin deposits enhance endothelial permeability; this effect allows subendothelial accumulation of lipid and foam cells.
Temporal Dissociation between Myeloperoxidase (MPO)-Modified LDL and MPO Elevations during Chronic Sleep Restriction and Recovery in Healthy Young Men
Karim Zouaoui Boudjeltia, Brice Faraut, Maria José Esposito, Patricia Stenuit, Michal Dyzma, Pierre Van Antwerpen, Dany Brohée, Luc Vanhamme, Nicole Moguilevsky, Michel Vanhaeverbeek, Myriam Kerkhofs
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0028230
Abstract: Objectives Many studies have evaluated the ways in which sleep disturbances may influence inflammation and the possible links of this effect to cardiovascular risk. Our objective was to investigate the effects of chronic sleep restriction and recovery on several blood cardiovascular biomarkers. Methods and Results Nine healthy male non-smokers, aged 22–29 years, were admitted to the Sleep Laboratory for 11 days and nights under continuous electroencephalogram polysomnography. The study consisted of three baseline nights of 8 hours sleep (from 11 pm to 7 am), five sleep-restricted nights, during which sleep was allowed only between 1 am and 6 am, and three recovery nights of 8 hours sleep (11 pm to 7 am). Myeloperoxidase-modified low-density lipoprotein levels increased during the sleep-restricted period indicating an oxidative stress. A significant increase in the quantity of slow-wave sleep was measured during the first recovery night. After this first recovery night, insulin-like growth factor-1 levels increased and myeloperoxidase concentration peaked. Conclusions We observed for the first time that sleep restriction and the recovery process are associated with differential changes in blood biomarkers of cardiovascular disease.
A New Device to Mimic Intermittent Hypoxia in Mice
Kamil J. Chodzyński, Stephanie Conotte, Luc Vanhamme, Pierre Van Antwerpen, Myriam Kerkhofs, J. L. Legros, Michel Vanhaeverbeek, Alain Van Meerhaeghe, Gregory Coussement, Karim Zouaoui Boudjeltia, Alexandre Legrand
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0059973
Abstract: Intermittent hypoxia (hypoxia-reoxygenation) is often associated with cardiovascular morbidity and mortality. We describe a new device which can be used to submit cohorts of mice to controlled and standardised hypoxia-normoxia cycles at an individual level. Mice were placed in individual compartments to which similar gas flow parameters were provided using an open loop strategy. Evaluations made using computational fluid dynamics were confirmed by studying changes in haemoglobin oxygen saturation in vivo. We also modified the parameters of the system and demonstrated its ability to generate different severities of cyclic hypoxemia very precisely, even with very high frequency cycles of hypoxia-reoxygenation. The importance of the parameters on reoxygenation was shown. This device will allow investigators to assess the effects of hypoxia–reoxygenation on different pathological conditions, such as obstructive sleep apnoea or chronic obstructive pulmonary disease.
Myeloperoxidase-Dependent LDL Modifications in Bloodstream Are Mainly Predicted by Angiotensin II, Adiponectin, and Myeloperoxidase Activity: A Cross-Sectional Study in Men
Karim Zouaoui Boudjeltia,Cédric Delporte,Pierre Van Antwerpen,Thierry Franck,Didier Serteyn,Nicole Moguilevsky,Martine Raes,Luc Vanhamme,Michel Vanhaeverbeek,Alain Van Meerhaeghe,Thierry Roumeguère
Mediators of Inflammation , 2013, DOI: 10.1155/2013/750742
Abstract: The present paradigm of atherogenesis proposes that low density lipoproteins (LDLs) are trapped in subendothelial space of the vascular wall where they are oxidized. Previously, we showed that oxidation is not restricted to the subendothelial location. Myeloperoxidase (MPO), an enzyme secreted by neutrophils and macrophages, can modify LDL (Mox-LDL) at the surface of endothelial cells. In addition we observed that the activation of the endothelial cells by angiotensin II amplifies this process. We suggested that induction of the NADPH oxidase complex was a major step in the oxidative process. Based on these data, we asked whether there was an independent association, in 121 patients, between NADPH oxidase modulators, such as angiotensin II, adiponectin, and levels of circulating Mox-LDL. Our observations suggest that the combination of blood angiotensin II, MPO activity, and adiponectin explains, at least partially, serum Mox-LDL levels. 1. Introduction Atherosclerosis is an inflammatory disease involving a crosstalk between vascular cells, monocytes, proinflammatory cytokines, chemokines, and growth factors [1–3]. The current paradigm of early atherosclerosis claims that low-density lipoprotein (LDL) particles are trapped in the subendothelial space of the vascular wall where they can be oxidized. The precise physiological process for LDL oxidation in vivo is still largely unknown and the occurrence of LDL oxidation outside the lesion sites has not definitively been ruled out yet. Evidence accumulated during the last decade has suggested implication of myeloperoxidase (MPO) in inflammation leading to atherogenesis. MPO is produced by macrophages and neutrophils [4] and via its chlorination activity, MPO produces hypochlorous acid (HOCl) from hydrogen peroxide (H2O2) and chloride anion (Cl?). HOCl can oxidize protein-bound amino acid residues among which the formation of 3-chlorotyrosine is considered as specific of the activity of MPO as the latter is the only human enzyme able to produce HOCl. In the context of atherogenesis, MPO, 3-chlorotyrosine, and MPO-dependent modified LDL (Mox-LDL) have all been detected in human atherosclerotic lesions and in the bloodstream [5–8]. We previously demonstrated that Mox-LDL generation could occur in vitro at the surface of the endothelial cells suggesting that it was not restricted to the subendothelial space in vivo [9]. The triad made up by endothelial cell, circulating LDL and MPO, allowed a synergic mechanism for producing Mox-LDL. The starting point of this reaction is the generation of superoxide anion ( )
A physical description of the adhesion and aggregation of platelets
Bastien Chopard,Daniel Ribeiro de Sousa,Jonas Latt,Frank Dubois,Catherine Yourassowsky,Pierre Van Antwerpen,Omer Eker,Luc Vanhamme,David Perez-Morga,Guy Courbebaisse,Karim Zouaoui Boudjeltia
Quantitative Biology , 2015,
Abstract: The early stages of clot formation in blood vessels involve platelets adhesion-aggregation. Although these mechanisms have been extensively studied, gaps in their understanding still persist. We have performed detailed in-vitro experiments and developed a numerical model to better describe and understand this phenomenon. Unlike previous studies, we took into account both activated and non-activated platelets, as well as the 3D nature of the aggregation process. Our investigation reveals that blood albumin is a major parameter limiting platelet adhesion and aggregation. Our results also show that the well accepted Zydney-Colton shear-induced diffusivity is much too low to explain the observed deposition rate. Simulations are in very good agreement with observations and provide quantitative estimates of the adhesion and aggregation rates that are hard to measure experimentally.
Variability and Action Mechanism of a Family of Anticomplement Proteins in Ixodes ricinus
Bernard Couvreur, Jér?me Beaufays, Cédric Charon, Kathia Lahaye, Fran?ois Gensale, Valérie Denis, Beno?t Charloteaux, Yves Decrem, Pierre-Paul Prév?t, Michel Brossard, Luc Vanhamme, Edmond Godfroid
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0001400
Abstract: Background Ticks are blood feeding arachnids that characteristically take a long blood meal. They must therefore counteract host defence mechanisms such as hemostasis, inflammation and the immune response. This is achieved by expressing batteries of salivary proteins coded by multigene families. Methodology/Principal Findings We report the in-depth analysis of a tick multigene family and describe five new anticomplement proteins in Ixodes ricinus. Compared to previously described Ixodes anticomplement proteins, these segregated into a new phylogenetic group or subfamily. These proteins have a novel action mechanism as they specifically bind to properdin, leading to the inhibition of C3 convertase and the alternative complement pathway. An excess of non-synonymous over synonymous changes indicated that coding sequences had undergone diversifying selection. Diversification was not associated with structural, biochemical or functional diversity, adaptation to host species or stage specificity but rather to differences in antigenicity. Conclusions/Significance Anticomplement proteins from I. ricinus are the first inhibitors that specifically target a positive regulator of complement, properdin. They may provide new tools for the investigation of role of properdin in physiological and pathophysiological mechanisms. They may also be useful in disorders affecting the alternative complement pathway. Looking for and detecting the different selection pressures involved will help in understanding the evolution of multigene families and hematophagy in arthropods.
Ir-LBP, an Ixodes ricinus Tick Salivary LTB4-Binding Lipocalin, Interferes with Host Neutrophil Function
Jér?me Beaufays, Beno?t Adam, Catherine Menten-Dedoyart, Laurence Fievez, Amélie Grosjean, Yves Decrem, Pierre-Paul Prév?t, Sébastien Santini, Robert Brasseur, Michel Brossard, Michel Vanhaeverbeek, Fabrice Bureau, Ernst Heinen, Laurence Lins, Luc Vanhamme, Edmond Godfroid
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0003987
Abstract: Background During their blood meal, ticks secrete a wide variety of proteins that can interfere with their host's defense mechanisms. Among these proteins, lipocalins play a major role in the modulation of the inflammatory response. Methodology/Principal Findings We previously identified 14 new lipocalin genes in the tick Ixodes ricinus. One of them codes for a protein that specifically binds leukotriene B4 with a very high affinity (Kd: ±1 nM), similar to that of the neutrophil transmembrane receptor BLT1. By in silico approaches, we modeled the 3D structure of the protein and the binding of LTB4 into the ligand pocket. This protein, called Ir-LBP, inhibits neutrophil chemotaxis in vitro and delays LTB4-induced apoptosis. Ir-LBP also inhibits the host inflammatory response in vivo by decreasing the number and activation of neutrophils located at the tick bite site. Thus, Ir-LBP participates in the tick's ability to interfere with proper neutrophil function in inflammation. Conclusions/Significance These elements suggest that Ir-LBP is a “scavenger” of LTB4, which, in combination with other factors, such as histamine-binding proteins or proteins inhibiting the classical or alternative complement pathways, permits the tick to properly manage its blood meal. Moreover, with regard to its properties, Ir-LBP could possibly be used as a therapeutic tool for illnesses associated with an increased LTB4 production.
A Trypanosoma brucei Kinesin Heavy Chain Promotes Parasite Growth by Triggering Host Arginase Activity
Géraldine De Muylder,Sylvie Daulouède,Laurence Lecordier,Pierrick Uzureau,Yannick Morias,Jan Van Den Abbeele,Guy Caljon,Michel Hérin,Philippe Holzmuller,Silla Semballa,Pierrette Courtois,Luc Vanhamme,Beno?t Stijlemans,Patrick De Baetselier,Michael P. Barrett,Jillian L. Barlow,Andrew N. J. McKenzie,Luke Barron,Thomas A. Wynn,Alain Beschin ? ,Philippe Vincendeau ?,Etienne Pays ?
PLOS Pathogens , 2013, DOI: 10.1371/journal.ppat.1003731
Abstract: Background In order to promote infection, the blood-borne parasite Trypanosoma brucei releases factors that upregulate arginase expression and activity in myeloid cells. Methodology/Principal findings By screening a cDNA library of T. brucei with an antibody neutralizing the arginase-inducing activity of parasite released factors, we identified a Kinesin Heavy Chain isoform, termed TbKHC1, as responsible for this effect. Following interaction with mouse myeloid cells, natural or recombinant TbKHC1 triggered SIGN-R1 receptor-dependent induction of IL-10 production, resulting in arginase-1 activation concomitant with reduction of nitric oxide (NO) synthase activity. This TbKHC1 activity was IL-4Rα-independent and did not mirror M2 activation of myeloid cells. As compared to wild-type T. brucei, infection by TbKHC1 KO parasites was characterized by strongly reduced parasitaemia and prolonged host survival time. By treating infected mice with ornithine or with NO synthase inhibitor, we observed that during the first wave of parasitaemia the parasite growth-promoting effect of TbKHC1-mediated arginase activation resulted more from increased polyamine production than from reduction of NO synthesis. In late stage infection, TbKHC1-mediated reduction of NO synthesis appeared to contribute to liver damage linked to shortening of host survival time. Conclusion A kinesin heavy chain released by T. brucei induces IL-10 and arginase-1 through SIGN-R1 signaling in myeloid cells, which promotes early trypanosome growth and favors parasite settlement in the host. Moreover, in the late stage of infection, the inhibition of NO synthesis by TbKHC1 contributes to liver pathogenicity.
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